Although considerable progress has been made in delineating MRI gray matter abnormalities in schizophrenia, relatively little progress has been made in evaluating white matter abnormalities, or the white matter fiber tract connections between gray matter regions, particularly those that connect the frontal and temporal lobes. These tracts that have long been thought to be abnormal in schizophrenia. Many subsequent investigators have hypothesized some type of connectivity deficit or disconnection model of schizophrenia. We plan to explicitly investigate such anomalies in this proposal. The overarching aim of this three-year proposal is to investigate abnormalities of connectivity at an anatomic and functional level in schizophrenia. Accordingly, we plan to employ a novel and integrative approach to investigating abnormal brain connectivity in schizophrenia, including an analysis of white matter fiber tract abnormalities, as well as the network nodes that these pathways interconnect. As a Driving Biological Project (DBP), this integrative aim will require the highly advanced computational strategies and robust software implementation provided by other subprojects in this grant. This project will emphasize MR Diffusion Tensor Imaging (DTI), a relatively new MR imaging technique that affords a unique opportunity to investigate and quantify white matter abnormalities in the brain. It will also include functional MRI (fMRI) probes of working, episodic, and semantic memory systems known to be abnormal in schizophrenia. Our use of fMRI will focus specifically on connectivity among regions implicated in the pathophysiology of schizophrenia using memory activation tasks to bring out the hypothesized abnormalities. An event related verbal episodic encoding and recognition memory task will target prefrontal and medial temporal sites. This task was developed based on our prior fMRI experience in normals and in patients with known seizure foci undergoing surgical treatment. Earlier evidence using electrophysiological methods suggested sensitivity of similar experiments to frontal vs. temporal lobe lesion location and numerous PET and fMRI studies have implicated these regions in schizophrenia. We will investigate the working memory system with fMRI using the n-back paradigm which has been shown by our group to robustly activate the prefrontal and parietal cortex in neurological patients and controls. Similar results in healthy controls have been widely reported in the PET and fMRI literature. In the present study, this task will afford us an opportunity to examine fronto-parietal connectivity and basal ganglia sites of interest that are also often activated. Finally, an event-related semantic memory task patterned after our earlier blocked design experiments will be used to activate left inferior prefrontal and left superior temporal regions of interest (ROIs). The broader PET and fMRI literature typically implicates these sites for language and semantic memory retrieval. These leading edge technologies will be integrated with volumetric and shape analyses of implicated gray matter structures as well as clinical and neurocognitive assessments to fully characterize the sample. In addition, although not the focus of this project, we will also collect blood from all subjects for genetic analysis.